X-linked lymphoproliferative syndrome (XLP) is characterized by three prevalent phenotypes: 1) Fulminant Infectious Mononucleosis, 2) malignant B cell lymphoma and 3) acquired hypogammaglobulinema in the absence of infectious mononucleosis. As the three major phenotypes of XLP are found within one family harboring the same mutation, genetic background and/or environmental factors must play a role in the pathogenesis of the disease. FIM patients mount a vigorous, uncontrolled polyclonal expansion of T and B cells, inevitably leading to death by hepatic necrosis and bone marrow failure. A major cause of XLP in humans is a defect in the SH2D1A gene, which encodes SAP (SLAM Associated Protein), a single free SH2- domain protein that controls distinct key signal transduction pathways in CD4 and CDS T lymphocytes, NK cells, platelets and probably a subset of B cells. SAP functions as an adapter, which bridges the cytoplasmic tail of six members of the SLAM receptor family to signal transduction pathways, e.g. Fyn and other tyrosine kinases. Previous studies show that several arms of the acquired immune responses are affected in XLP patients and SAP-deficient mice and that the SAP related molecules EAT-2A and -2B subserve similar functions. Our general hypothesis is that SAP and EAT-2A/B control partially overlapping mechanisms that are critical for the control of humoral immunity. The experiments proposed in this application will test the hypothesis that #1) distinct SAP-/- CD4+ T cell subsets and/or NKT cells contribute to the dysgammaglobulinemia of SAP-/- mice, #2) disruption of the SAP gene affects the subsets of follicular B cells, which participate in humoral responses and in the germinal center reaction and #3) EAT-2A/B and SAP interact in the control of antibody responses. Together these experiments should clarify the role of SAP and EAT-2 in T cell dependent B cell responses and why the absence of SAP functions causes dys-gammaglobulinemia. The results of these studies should suggest therapeutic strategies that can be applied to XLP patients.